ICB Seminar

08.07.2019

Dissecting the polygenic basis of schizophrenia using functional genomics and patient specific induced pluripotent stem cell models

Dr. Michael Ziller, MPI of Psychiatry
ICB Seminar room 121 at 11:30

Despite astonishing advances in the genetic characterization of complex diseases, it has been challenging to pinpoint the exact molecular mechanisms that lead to disease onset and progression. These difficulties are rooted in the highly polygenic architecture of these diseases, the fact that most disease associated genetic variants reside in the non-coding space of the genome and the inaccessibility of suitable human model systems.

These challenges are particularly pronounced in the case of psychiatric diseases such as schizophrenia which mainly affect cells of the nervous system.

In my talk, I will present our efforts to establish an analytical and experimental pipeline to address these challenges and deconstruct how polygenic risk can drive changes in cellular endophenotypes in disease relevant cell populations.

In particular, I will discuss our standardized in vitro differentiation system of induced pluripotent stem cells (iPSC) from patients with psychiatric diseases as a model system for polygenic risk. Using this system, combined with a medium throughput platform for molecular, cellular and circuit level endophenotyping, we identified alterations in multiple endophenotypes between patients and healthy donors in iPSC derived neurons. In order to pinpoint the precise disease associated genetic variants that drive these changes, we combine this modeling platform with functional genomic screening strategies based on (sc-)RNA-Seq, ATAC-Seq, chromatin conformation capture by HiC, massively parallel reporter assays and computational modeling. Finally, we evaluate potential hit candidates using genetically engineered dCas9-Effector iPSC lines combined with massively parallel gain/loss of function screening in iPSC derived neurons using CROP-Seq and traditional genome editing

 

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